Primary brain tumors were responsible for 11,800 deaths in the US in 1992. Brain tumors are second only to leukemia as the leading cause of cancer death among children younger than 15 yr. of age, and the 4th most frequent cause among men 15-35 yr. old. While fewer women are afflicted overall, they made up 46% of the estimated 16,900 patients with new brain tumors diagnosed in 1992. If the many other forms of cancer that metastasize to the brain are added, the number of patients with brain tumors rises significantly, and the incidence of these lesions in people over 65 yr. of age is increasing. Surgery is the primary treatment for brain malignancy but for most patients, only subtotal resection of tumor can be achieved; adjuvant treatment is needed to impede tumor regrowth. The Brain Tumor Research Center (BTRC) has developed into a major treatment center for patients with tumors of the brain. The BTRC's long-term objective is to cure malignant brain tumors. To achieve it requires us to understand the biology of the disease and attack it at the basis of underlying genetic deficiencies. In the short term, our goals are to improve existing brain tumor therapies and develop new and more effective therapeutic approaches. This proposal targets radiation, the most effective treatment for malignant lesions after surgery, and glioblastoma multiforme (GBM), the most aggressive malignant lesion in the brain. Our overall hypothesis is that the clinical results of radiation therapy can be improved markedly by refining existing radiation therapy protocols, by identifying tumors that are resistant to radiation before patients undergo radiation therapy, and by ameliorating or overcoming cellular resistance to radiation. The interrelated projects that compose our research program are integrated in a single theme: escalation of clinical efficacy of radiation therapy for GBM to the maximum level possible within the next 5 yr. Prados' project includes the clinical trials for adult patients. Feuerstein and Deen will identify patients with radiation-resistant GBM at surgery so that alternative therapies can be considered. Feuerstein will provide important genetic information for categorizing brain tumors. Bodell will determine the relationship between radiation resistance and resistance to nitrosoureas; it will identify those patients whose tumors will be refractory to nitrosourea therapy alone. Fike will define the critical radiation dose-volume relationships for radiosurgery, so that clinical treatments provided by using this modality can be optimized for safety and efficacy. Chan will define the role that oxidative stress plays in radiation-induced injury to endothelial cells, the critical dose-limiting tissues for therapy. Israel will investigate the genetic determinants and biochemical pathways involved in cell cycle delays that are important in overall cellular radiation-induced damage.